ArticleThe Journal of biological chemistry2014
Characterization and structure of the vaccinia virus NF-κB antagonist A46.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 32 citations in OpenAlex.
- African swine fever virus-encoded protein MGF 505-3R impairs innate immunity via ubiquitin-mediated degradation of MyD88.Communications biology · 2026Article
- Transcriptome Changes in Glioma Cells upon Infection with the Oncolytic Virus VV-GMCSF-Lact.Cells · 2023Article
- Poxviruses and the immune system: Implications for monkeypox virus.International immunopharmacology · 2022Review
- Viral-mediated activation and inhibition of programmed cell death.PLoS pathogens · 2022Review
- Poxviral Strategies to Overcome Host Cell Apoptosis.Pathogens (Basel, Switzerland) · 2020Review
- Review
- Leaky scanning translation generates a second A49 protein that contributes to vaccinia virus virulence.The Journal of general virology · 2020Article
- The Bcl-2 Family: Ancient Origins, Conserved Structures, and Divergent Mechanisms.Biomolecules · 2020Review
- NF-κB activation is a turn on for vaccinia virus phosphoprotein A49 to turn off NF-κB activation.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Review
- The Bcl-2 Family in Host-Virus Interactions.Viruses · 2017Review
- Vaccinia Virus Immunomodulator A46: A Lipid and Protein-Binding Scaffold for Sequestering Host TIR-Domain Proteins.PLoS pathogens · 2016Article
- Multiple Bcl-2 family immunomodulators from vaccinia virus regulate MAPK/AP-1 activation.The Journal of general virology · 2016Article
- Surfing the Protein-Protein Interaction Surface Using Docking Methods: Application to the Design of PPI Inhibitors.Molecules (Basel, Switzerland) · 2015Review
- Vaccinia virus protein A49 is an unexpected member of the B-cell Lymphoma (Bcl)-2 protein family.The Journal of biological chemistry · 2015Article
- TRAM is required for TLR2 endosomal signaling to type I IFN induction.Journal of immunology (Baltimore, Md. : 1950) · 2014Article
- Vaccinia virus virulence factor N1 can be ubiquitylated on multiple lysine residues.The Journal of general virology · 2014Article
- Structure of vaccinia virus A46, an inhibitor of TLR4 signaling pathway, shows the conformation of VIPER motif.Protein science : a publication of the Protein Society · 2014Article
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
Successful vaccinia virus (VACV) replication in the host requires expression of viral proteins that interfere with host immunity, such as antagonists of the activation of the proinflammatory transcription factor NF-κB. Two such VACV proteins are A46 and A52. A46 interacts with the Toll-like receptor/interleukin-1R (TIR) domain of Toll-like receptors and intracellular adaptors such as MAL (MyD88 adapter-like), TRAM (TIR domain-containing adapter-inducing interferon-β (TRIF)-related adaptor molecule), TRIF, and MyD88, whereas A52 binds to the downstream signaling components TRAF6 and IRAK2. Here, we characterize A46 biochemically, determine by microscale thermophoresis binding constants for the interaction of A46 with the TIR domains of MyD88 and MAL, and present the 2.0 Å resolution crystal structure of A46 residues 87-229. Full-length A46 behaves as a tetramer; variants lacking the N-terminal 80 residues are dimeric. Nevertheless, both bind to the Toll-like receptor domains of MAL and MyD88 with KD values in the low μm range. Like A52, A46 also shows a Bcl-2-like fold but with biologically relevant differences from that of A52. Thus, A46 uses helices α4 and α6 to dimerize, compared with the α1-α6 face used by A52 and other Bcl-2 like VACV proteins. Furthermore, the loop between A46 helices α4-α5 is flexible and shorter than in A52; there is also evidence for an intramolecular disulfide bridge between consecutive cysteine residues. We used molecular docking to propose how A46 interacts with the BB loop of the TRAM TIR domain. Comparisons of A46 and A52 exemplify how subtle changes in viral proteins with the same fold lead to crucial differences in biological activity.
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